Serotonin type 3 (5HT3) receptors are part of the serotonergic system. Unlike other receptors of this system, which are all G-protein coupled receptors, the 5HT3 receptors are ligand-gated ion channels and belongs to the superfamily of Cys-loop receptors that include nicotinic acetylcholine, γ-aminobutyric acid (GABA)A and glycine receptors and a Zn+2 activated cation channel (see Davies et al., 2003, J. Biol. Chem., 278, 712-717; Connolly et al., 2004, Biochem Soc Trans 32, 529-534). The 5HT3 receptors are made up of 5 subunits arranged around a central ion conducting pore, which is permeable to sodium, potassium, and calcium ions (see Boess et al., 1995, J. Neurochem. 64, 1401-1405; Connolly et al., 2004, Biochem Soc Trans 32, 529-534). Binding of serotonin to the 5HT3 receptors opens the channel, which, in turn, leads to an excitatory response in neurons. Functional data reported for 5HT3 receptors refer to 5HT3A or 5HT3AB receptors since the properties of these receptor subtypes have been most extensively studies to date.
5HT3 receptors are known to be expressed in the central nervous system in regions involving vomiting reflex, processing of pain, cognition and anxiety control and play a role in the pathogenesis of diseases such as emesis, migraine, drug addiction, and neurodegenerative and psychiatric disorders such as anxiety and depression (see Hewlett et al., 2003 J. Clin. Psychiatry 64, 1025-1030; Kelley et al., 2003a, Eur J. Pharmacol., 461, 19-25; Haus et al., 2000 Scand J Rheumatol Suppl 113, 55-58; and Faris et al., 2006 J affect Disorder 92, 79-90), eating disorders (Hammer et al., 1990 Am J Physiol 259, R627-R636, and Jiang & Gietzen 1994 Pharmacol Biochem Behav 47, 59-63), schizophrenia (see Hermann et al. 1996 Biochem Biophys Res Commun 225, 957-960; Sirota et al., 2000 Am J Psychiatry 157, 287-289; Adler et al., 2005 Am J Psychiatry 162, 386-388; Koike et al., Levkovitz et al, 2005 Schizophr Res 76, 67-72), cognitive dysfunction associated with schizophrenia (see Zhang et al., 2006 Schizophr Res 88, 102-110; Akhondzadeh et al., 2009 Schizophr Res 107, 206-212), cognitive dysfunction associated with Parkinson's disease, Huntington's Chorea, presenile dementias and Alzheimer's disease (see Costall and Naylor 2004 CNS Neurol Disord 3, 27-37) substance abuse and addiction (see Johnson et al., 2002 Psycho-pharmacology (Berl) 160, 408-413; Johnson, 2004 CNS Drugs 18, 1105-1118; Dawes et al., 2005 Addict Behav 30, 1630-1637, Johnson 2006 Drug Alcohol Depend 84, 256-263), autish spectrum disorders (see Anderson et al Neurogenetics 10, 209-216) and pain (see Kayser et al, 2007 Pain 130, 235; Glaum et al., 1998 Neurosci Lett 95, 313-317; Schworer & Ramadori 1993 Clin Investig 71, 659; Thompson and Lummis 2007 Exp Opin Ther Targets, 11, 527-540). In addition, 5HT3 receptors are expressed in the GI tract and hence may play a role in GI disorders such as dyspepsia, gastroesophagal reflux disease and irritable bowel syndrome (see Graeff 1997 Psychiatr Clin North Am 20, 723; Thompson and Lummis 2007 Exp Opin Ther Targets, 11, 527-540; Barnes et al. 2009 Neuropharmacology 56, 273). Expression of the 5HT3A subsunit has also been discovered extraneuronally in immune cells such as monocyes, chondrocytes, T-cells, synovial tissue and platelets (Fiebich et al., 2004 Scan J Rheumatol Suppl, 9-11, Stratz et al., 2008 Thromb Haemost 99, 784) and of 5HT3A, C-E within the lamina propia in the epithelium of the gut mucose (Kapeller et al., J Comp Neuro., 2008; 509: 356-371) thus suggesting they may be involved in immunological and inflammatory diseases like atherosclerosis, tendomyopathies and fibromyalgia.
The 5HT3 antagonists currently on the market are approved only for the treatment of emesis or irritable bowel syndrome. It is desirable to discover 5HT3 antagonists that can be used to treat other diseases amenable to alleviation by 5HT3 receptors such as schizophrenia and cognitive disorder associated with schizophrenia. The present invention can fulfill this and related needs. It is desirable to discover 5HT3 antagonists that have desirable pharmacokinetic and pharmacodynamic properties, such as selectivity over nicotinic-α7 receptors.
Certain antagonists the 5HT3 receptor are described in U.S. Pat. Nos. 4,789,763; 4,803,199; 4,886,808; 4,910,193; 5,334,831; EP 0 469 449; and EP 0 491 664. Certain inhibitors of TGF-β are described in EP 1 156 045 and certain treatment of nephritis is described in EP1 243 268. Certain antagonists of 5HT4 are described in EP 0 708 105. Certain ligands of nicotinic-α7 receptors are described in WO 2007/038367. Certain P2X7 antagonists are disclosed in WO 2009/023623.